title: Inhibition of Wnt/β-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma.
abstract: The development of multi-drug resistance (MDR) represents a major obstacle in the successful treatment of cancers. However, the factors and mechanisms that lead to MDR in cholangiocarcinoma (CCA), a chemoresistant bile duct carcinoma with a poor prognosis, remain unclear. In this study, we established a human MDR CCA cell line QBC939/5-FU. Compared with QBC939 cells, a rounder shape, a higher nuclear-cytoplasmic ratio, a shorter cell cycle, faster growth and resistance to chemotherapeutics are major characteristics of QBC939/5-FU cells. P-glycoprotein (P-gp) and β-catenin were upregulated in QBC939/5-FU cells. Furthermore, the drug susceptibility of QBC939 cells to common chemotherapeutics was significantly decreased after Wnt3a treatment, whereas inhibition of Wnt/β-catenin pathway by β-catenin siRNA reversed the MDR of QBC939/5-FU cells to chemotherapeutics. Molecular study revealed that activation of Wnt/β-catenin pathway resulted in upregulation of P-gp and contributed to MDR of QBC939/5-FU cells. Extraction of Siamese Crocodile 3 (ESC-3) bile enhanced the drug sensitivity of QBC939/5-FU cells to 5-FU, paralleled with downregulation of β-catenin and P-gp. The association of Wnt/β-catenin pathway and P-gp was further confirmed by the clinical data for CCA tissues. Our study represents the first implication of Wnt/β-catenin activation in the MDR of CCA, which may be a beneficial target for the clinical treatment of CCA.
authors.affiliation: Center Laboratory, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Shen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Zeng
authors.forename: Chang-Qin
authors.initials: CQ
authors.lastname: Liu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis* / Q000235:genetics; D000489:Alligators and Crocodiles; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001646:Bile / Q000737:chemistry; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor / Q000187:drug effects; D048429:Cell Size; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D014020:Tissue Extracts / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D060509:Wnt3A Protein / Q000494:pharmacology; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D014020:Tissue Extracts; D060509:Wnt3A Protein; D051176:beta Catenin; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C495270:CTNNB1 protein, human; C555510:WNT3A protein, human